The principal goal of Kawas' Project is to understand the biological substrates of cognitive decline in elderly individuals. To this end, we will conduct comprehensive clinical and neuropsychological examinations on several cohorts of subjects representing the full spectrum of cognitive states associated with old age. Our cohorts include older individuals who are cognitively intact or have minimal cognitive deficits below the threshold for dementia, as well as patients in the early and late states of dementia. All of the individuals in our program have committed to donate tissues, obtained at autopsy, for research. The centerpiece of this Project is the cohort in the Baltimore Longitudinal Study of Aging (BLSA), about 4 subjects >65 years of age who have been followed longitudinally with detailed exams for many years. A wealth of medical/neurological information is available on these individuals. BLSA subjects enrolled in this Project will undergo thorough annual neurological/cognitive evaluations. Furthermore, many of these individuals will have annual brain MRI and PET scans as part of a collaborative, NIA-sponsored research study. Based on preliminary data, we anticipate that the majority of the BLSA subjects will remain cognitively intact but that some individuals will experience mild intellectual decline, and others will become demented. Postmortem examinations, obtained within one year after the last examination, focus on three areas: neuropathological examinations, with emphasis on delineating the evolution, distribution and abundance of the cellular lesions, A-beta deposits, senile plaques, and neurofibrillary tangles; stereological quantitative morphometry to estimate the total number of neurons and synapses in hippocampus and entorhinal cortex; and neurochemical measurements of cholinergic, monoaminergic, and glutamatergic systems in the hippocampus, entorhinal cortex, and neocortex. Based on the concept that the pathogenesis of dementia predates the onset of cognitive/memory deficits, we believe that our studies correlate clinical, laboratory, and imaging data with detailed neuropathological evaluations and neurochemical examinations will provide extraordinarily valuable information for understanding the biological substrates of age-associated cognitive abnormalities, including those that occur in AD.